Tropical protozoal infections are
a significant cause of morbidity
and mortality worldwide; four in particular (human African trypanosomiasis
(HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have
an estimated combined burden of over 87 million disability-adjusted
life years. New drugs are needed for each of these diseases. Building
on the previous identification of NEU-617 (1) as a potent
and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs
against other protozoal species: T. cruzi (Chagas
disease), Leishmania major (cutaneous leishmaniasis),
and Plasmodium falciparum (malaria). Based on hits
identified in this screening campaign, we describe the preparation
of several replacements for the quinazoline scaffold and report these
inhibitors’ biological activities against these parasites.
In doing this, we have identified several potent proliferation inhibitors
for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile
(NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine
(NEU-1017, 68) for L. major and P. falciparum.
Target repurposing is a proven method for finding new lead compounds that target Trypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog 2 with excellent potency against T. brucei (EC50 = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC50 of 84 nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas’ disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites.
Human African trypanosomiasis (HAT) is a deadly disease in need of new chemotherapeutics that can cross into the central nervous system. We previously reported the discovery of 2 (NEU-617), a small molecule with activity against T. brucei bloodstream proliferation. Further optimization of 2 to improve the physicochemical properties (LogP, LLE,[1] and MPO score)[2] have led us to twelve sub-micromolar compounds, most importantly the headgroup variants 9i and 9j, and the linker variant 18. Although these 3 compounds had reduced potency compared to 2, they all had improved LogP, LLE and MPO scores. Cross-screening these analogs against other protozoan parasites uncovered 9o with potent activity towards T. brucei, T. cruzi and L. major, while four others compounds (17, 18, 21, 26) showed activity towards P. falciparum D6. This reinforces the effectiveness of lead repurposing for the discovery of new protozoan disease therapeutics.
La Crosse (LAC) virus is transmitted horizontally to vertebrates and vertically to progeny by Aedes triseriatus mosquitoes, and in northern midwestern states, this virus overwinters in diapausing eggs of the vector. In Florida, the vector remains active throughout the year and does not diapause. To determine if there is an association between diapause and vertical transmission efficiency of LAC virus, transovarial transmission (TOT), and filial infection (FI) rates were determined for geographic strains of Ae. triseriatus. The TOT rates were not significantly different for Ae. triseriatus originating from Florida (78%) and those from Wisconsin (85%). The FI rates did differ significantly between the two groups (33% and 45%, respectively, for the Florida and Wisconsin mosquitoes). Furthermore, a line of mosquitoes was selected from a Wisconsin colony that had a reduced diapause phenotype (the AD Ϫ strain). While this strain displayed TOT rates that were the same as the other Wisconsin mosquitoes (85%), the FI rates were significantly lower (34%), indicating a reduction in TOT efficiency. The role of vertical transmission capacity in LAC virus endemicity remains to be determined.
Antiviral drug resistance in influenza infections has
been a major
threat to public health. To develop a broad-spectrum inhibitor of
influenza to combat the problem of drug resistance, we previously
identified the highly conserved E339...R416 salt bridge of the nucleoprotein
trimer as a target and compound 1 as an inhibitor disrupting
the salt bridge with an EC50 = 2.7 μM against influenza
A (A/WSN/1933). We have further modified this compound via a structure-based
approach and performed antiviral activity screening to identify compounds 29 and 30 with EC50 values of 110
and 120 nM, respectively, and without measurable host cell cytotoxicity.
Compared to the clinically used neuraminidase inhibitors, these two
compounds showed better activity profiles against drug-resistant influenza
A strains, as well as influenza B, and improved survival of influenza-infected
mice.
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